Many signaling pathways that are mutated in human cancer are evolutionarily conserved. Genetic studies of these pathways in model organisms may yield insights into cancer pathogenesis. The candidate is an M.D.-Ph.D. with a strong background in signal transduction research. He has recently completed a medical oncology fellowship and seeks to establish a career as an independent physician-scientist by using C. elegans as a genetic model system to study evolutionarily conserved signaling pathways that are deranged in cancer. As proof of principle, he proposes to identify and characterize novel components of the C. elegans DAF-18/PTEN signaling pathway in the laboratory of Dr. Gary Ruvkun at MGH. The PTEN tumor suppressor is mutated in a wide variety of cancers. It antagonizes an oncogenic PI3-kinase/Akt signaling cascade by virtue of its 3-phosphoinositide phosphatase activity, preventing Akt kinase activation. Detailed molecular analysis of this pathway is critical to an improved understanding of tumorigenesis and the development of new treatments for diverse human cancers. Genetic analysis has identified six components of the DAF-18/PTEN signaling cascade in C. elegans, all of which are conserved in humans. Five of these molecules have been implicated in oncogenesis. This striking conservation indicates that insights gained from studying DAF-18/PTEN signaling in C. elegans will impact upon our understanding of cancer pathogenesis in humans. The research proposal is a multifaceted approach focused on the identification and characterization of novel components of DAF-18/PTEN signaling. It includes forward genetic, functional genomic, and RNAi-based strategies. By taking full advantage of the genetic tractability of C. elegans, the well- annotated and complete genome sequence, and the recent adaptation of RNAi to h i gh-throughput analysis, this approach should greatly accelerate our understanding of DAF-18/PTEN signaling.